Erectile dysfunction, or impotence, is a common disorder that occurs in more than 10 million men in the USA. Although psychogenic etiology was thought to be the primary cause of erectile dysfunction, it now is believed that underlying organic diseases are responsible for most instances of erectile dysfunction. This conceptual change is supported by the particularly high incidence of impotence in men with essential hypertension, coronary artery disease and diabetes. In addition, a major mechanism responsible for impotence is an increase in the tone and/or contractility of smooth muscle within the corpus cavernosum penis and penile arteries that impede the modulation of penile blood flow by physiologic regulators. A similar mechanism, an increased tone and/or contractility of vascular smooth muscle, impedes the modulation of blood flow in the coronary, renal, and other arteries of hypertensive, diabetic etc. patients.
Other potential organic causes of erectile dysfunction include endocrine disorders, e.g., testicular failure and hyperprolactinemia; side effects of drugs, e.g., antiandrogens, antihypertensives, anticholinergics, antidepressants, antipsychotics, central nervous system depressants and drugs of habituation or addiction; penile diseases, e.g., Peyronie's disease, previous priapism, and penile trauma; neurological diseases, e.g., anterior temporal lobe lesions, diseases of the spinal cord, loss of sensory input, diseases of nervi erigentes, and diabetic autonomic neuropathy; and vascular diseases, e.g., essential hypertension, aortic occlusion, atherosclerotic occlusion or stenosis of the pudendal artery, venous leak, and diseases of the sinusoid spaces.
Disorders such as essential hypertension, coronary artery disease and diabetes involve an increase in vascular smooth muscle tone which imposes limitations on the modulation of regional blood flow in the kidney, heart, brain and other segments of the vascular bed. Clinical and experimental observations suggest that an imbalance between locally produced Angiotensin II and nitric oxide (NO) leads to an inappropriate tone of vascular smooth muscle resulting in increased blood pressure and altered regional blood flow. Indeed, administrations of nitric oxide synthase (NOS) inhibitors or Angiotensin II increase the tone and/or contractility of vascular smooth muscle and systemic blood pressure, thereby decreasing regional blood flow to organs such as the kidney and heart. Conversely, NO, Angiotensin II antagonists, renin inhibitors, and angiotensin converting enzyme (ACE) inhibitors decrease the smooth muscle tone and increase regional blood flow to these organs, and decrease systemic blood pressure.
As a modified vascular tissue, corpus cavernosum penis (ccp) produces and secretes the same range of autocrine and paracrine regulators as conventional vascular tissue. The smooth muscle tone of the ccp, however, does not appear to be regulated in the same manner as in the vascular wall. Presently it is postulated that the tone or contractility of ccp is modulated by adrenergic regulation and locally produced NO and endothelin. In the ccp, most studies have been directed to observing the relaxing effects of NO, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and parasympathetic innervation, which also have similar effects on conventional and ccp vascular smooth muscle.
Recently, it was discovered that renin-angiotensin system inhibitors, similar to the vascular tissue, the corpus cavernosum penis produces and secretes Angiotensin II, that plays an important role in modulation of the penile blood flow (PCT International Patent Application WO97/10821). Local, intracavemosal, or systemic administration of Angiotensin II antagonists or ACE inhibitors has a powerful effect on the penile blood flow. This effect can be used to improve erectile dysfunction without the inconvenience and side effects of drugs used for intracavernosal pharmacotherapy. Although the use of renin-angiotensin system inhibitors for treating impotence drastically improved the therapeutic options available to men experiencing impotence problems, it would be even more desirable to have an additional therapeutic method for treating impotence.